Genetic Modulation of HbF in Beta Thalassemia

β 地中海贫血中 HbF 的基因调节

• 批准号: 6987112
• 负责人: DAVID H K CHUI
• 金额: $ 59.21万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6987112
• 关键词: biotechnology; blood disorder diagnosis; cell differentiation; clinical research; erythrocytes; family genetics; functional /structural genomics; gene expression; gene mutation; genetic carriers; genetic polymorphism; genetic regulatory element; genetic screening; genetic susceptibility; hemoglobin F; high performance liquid chromatography; human genetic material tag; linkage disequilibriums; linkage mapping; nucleic acid sequence; quantitative trait loci; regulatory gene; single nucleotide polymorphism; statistics /biometry; thalassemia; biotechnology; blood disorder diagnosis; cell differentiation; clinical research; erythrocytes; family genetics; functional /structural genomics; gene expression; gene mutation; genetic carriers; genetic polymorphism; genetic regulatory element; genetic screening; genetic susceptibility; hemoglobin F; high performance liquid chromatography; human genetic material tag; linkage disequilibriums; linkage mapping; nucleic acid sequence; quantitative trait loci; regulatory gene; single nucleotide polymorphism; statistics /biometry; thalassemia

DESCRIPTION (provided by applicant): Thalassemias are man's most common Mendelian trait. Severe beta-thalassemia results from compound heterozygosity or homozygosity for mutations that abolish or impair beta-globin gene expression. The disease severity varies considerably, even among those with identical beta-thalassemia mutations and when known epistatic genetic factors, such as alpha-thalassemia, are considered. Most of this heterogeneity can be linked to the capacity to produce HbF. We hypothesize that there is genetic variation in cis-acting elements and trans-acting factors implicated in gamma-globin gene expression, in modulation of HbF concentration within erythrocytes, and in regulation of erythroid cell differentiation and proliferation. We wish to identify these genetic variations. Our 1st aim is to identify informative single nucleotide polymorphisms (SNPs) and haplotype structures in about 150 candidate genetic loci, by studying 30 family triads, each with 2 parents and 1 child. Using the haplotype tagging SNPs discovered in aim 1, our 2nd aim is to discover genetic loci and genes associated with F-cell/HbF levels, by studying about 1,000 beta-thalassemia carriers. SNP and haplotype data will be used in an F-cell/HbF quantitative trait locus (QTL) analysis. The 3rd aim is to correlate the genetic loci and genes found to be associated with F-cell/HbF levels to disease phenotypes, by studying about 320 severe beta-thalassemia patients. Our long-term goal is to identify genes of importance in HbF expression, and to investigate their biological and pathophysiological functions. A patient registry of sufficient size to accomplish these aims has been established in Hong Kong. We have formed an interactive and cohesive team of pediatricians, hematologists, geneticists, molecular biologists, epidemiologists, bioinformaticians, and statisticians who together are experienced in the proposed clinical/genetic approaches. The results of this investigation will prepare us to understand the function of potentially important genes for HbF regulation, develop prognostic guidelines and identify new therapeutic targets.

描述（由申请人提供）：thalassemias是人类最常见的门德尔特征。严重的β-甲0ALAMEASIA是由于消除或损害β-珠蛋白基因表达的突变而产生的。即使在患有相同β-甲性贫血突变的患者中，也考虑了疾病的严重程度有很大的不同，并且考虑到已知的上毒遗传因素（例如α-丘脑贫血）。这种异质性的大部分都可以与产生HBF的能力有关。我们假设顺式作用元件和跨作用因子存在遗传差异，与γ-球蛋白基因表达，红细胞内HBF浓度的调节以及红细胞分化和增殖的调节有关。我们希望确定这些遗传变异。我们的第一个目的是通过研究30个家庭三合会，每个家庭有2个父母和1个孩子，以确定约150个候选遗传基因座的信息单核苷酸多态性（SNP）和单倍型结构。使用在AIM 1中发现的单倍型标记SNP，我们的第二个目标是通过研究约1,000个β-甲基硫酸盐载体来发现与F细胞/HBF水平相关的遗传基因座和与F细胞/HBF水平相关的基因。 SNP和单倍型数据将用于F细胞/HBF定量性状基因座（QTL）分析中。第三个目的是通过研究约320名严重的β-核阿无血症患者，将发现与F细胞/HBF水平相关的遗传基因座和基因与疾病表型相关联。我们的长期目标是确定HBF表达中重要性的基因，并研究其生物学和病理生理功能。在香港已经建立了足够大小的患者注册表以实现这些目标。我们组成了一个由儿科医生，血液学家，遗传学家，分子生物学家，流行病学家，生物信息学家和统计学家组成的互动和凝聚力团队，他们在拟议的临床/遗传方法中共同经验丰富。这项研究的结果将使我们能够理解潜在的重要基因在HBF调节中的功能，制定预后指南并确定新的治疗靶标。